The Doctor Weighs In

By Dov Michaeli MD, Ph.D

It is a well-known phenomenon: people under stress hit the fridge, and gorge on candy and fatty food. A gallon of ice scream in one sitting is not unheard of. But people who think deeply about such things asked themselves: why don’t they (people under stress) gorge on veggies? And what is the nature of the connection between stress and obesity? Is it simply overeating equalsobesity, or is there a deeper connection, involving the brain? After all, stress is a mind thing.

The physiology of acute stress

Almost every physiological action in our body is controlled by two systems: the autonomic nervous system, and the endocrine system.

The autonomic nervous system has this name because it is, well, autonomic: it marches to its own drum, if you will, independently of our whims, wishes or commands. This system is made up of two sub-systems: the sympathetic and the parasympathetic. Basically, they are the Yin and Yang of the autonomic nervous system: the sympathetic nerves secrete noradrenaline, a close relative of adrenaline, and it does everything you’d expect it to do: it accelerates the heart rate, increases blood pressure, in short: it readies the body to react to acute stress situations. My favorite example: you spot a lion coming at you. You want to supply ample blood to your muscles so you can run for your life, or if you are foolish enough, fight the lion; hence the increase in heart rate and blood pressure. The parasympathetic system secretes the neurotransmitter acetyl choline , and it has exactly the opposite action: it slows down the heart and reduces blood pressure.

The endocrine system reacts to stress by releasing two ‘stress hormones’: cortisol from the brain and adrenaline from the adrenal gland. Their action is similar to that of the sympathetic nervous system: increase blood pressure and heart rate.

The other type of stress

So far so good; but how does increased heart rate cause obesity? The answer is: it doesn’t. What I just described is the response to acute stress, and our bodies are well-adapted to handle it. But modern life added another type of stress: chronic stress. And here, a peptide, called neuropeptide Y, or NPY, comes into play. Its existence has been known for several years, but its function was largely unknown. It is expressed throughout the brain, but is especially abundant in circuits that regulate feeding and response to stress. Not surprisingly, like many other brain hormones, it is also secreted in tissues outside the brain that are involved in metabolism; it is secreted by sympathetic nerve endings in adipose tissue. Its function there has only recently been defined by Kuo and his coworkers. It increases adipogenesis (formation of fat tissue) by triggering both the formation of new adipocytes (fat cells) from immature preadipocytes, and by increasing the blood supply to the adipose tissue by formation of new blood vessels (a process called angiogenesis). Even more intriguing: the new fat tissue was not formed just anywhere in the body; it was formed in the abdomen, and specifically around the internal organs of the abdomen. This is exactly the fat distribution that is implicated in the genesis of metabolic syndrome. And to clinch the case: it does it only under severe chronic stress conditions. When mice were subjected to 2 threatening and severe chronic stress protocols, they secreted NPY; when they were subjected to non-threatening mild stress—no NPY. In biological experiments demonstration of a relationship between the “dose” (e.g. severity of the chronic stress) and “response” (e.g. secretion of the peptide), lends credibility to the observation, simply because in biology almost everything is dose-dependent.

Why do we prefer sweets and fats?

The mice in the experiment secreted NPY only if allowed to eat fatty or sugary food. Regular mouse chow did not support secretion of the hormone even under severe chronic stress conditions. We know that high calorie food triggers the reward circuits in the brain. In fact, chronic feeding of high calorie foods activates all the circuits and brain centers that are involved in addiction. That, in turn, induces more eating, which increases the degree of addiction, which… you get the drift. Bottom line: obesity.

The details of the connection between secretion of NPY and high calorie food still need to be worked out. Why didn’t regular, low calorie food have the same effect? What are the specific neural circuits involved in this calorie/reward/peptide axis of evil? What is the mechanism for the specific accumulation of fat around internal organs? Will withdrawal of high-calorie food result in reversal of the accumulation of fat back to normal?

Obviously, many unanswered questioned are triggered by this research. But this is the hallmark of good science: every answer raises many more questions.

In summary

NPY is the link between stress and obesity. Its action:

• Secreted from the sympathetic nervous system only under conditions of chronic severe stress
• Increases adipogenesis by triggering adipocytes formation from preadipocytes, and by increasing blood supply to the adipose tissue
• Secreted only when high calorie diet is available
• Involves the activation of reward circuits in the brain
• And last but not least, it induced a state of metabolic syndrome (obesity, insulin resistance) in the experimental mice.

What is the relevance of this research to human obesity/metabolic syndrome?

Obviously, this phenomenon needs to be demonstrated in humans. Demonstration that NPY levels are markedly higher in chronically-stressed individuals will be a big step forward. Inhibition of secretion of NPY through drugs or stress reduction techniques will add weight to the hypothesis.

The big prize: demonstration of weight reduction through reduction of NPY secretion will be a boon to us and to our strained health care budget.

Here is a thought that may have occurred to you: can our increasingly stressful lifestyle be partly responsible for the obesity/metabolic syndrome epidemic?

Another thought: rather than wait for the results of these experiments to yield the ultimate proof, why not toss out all the sweets and high calorie foods, and stock the fridge with “good for you” veggies? No activation of the reward system in your brain=no NPY secretion. Not very appetizing solution, I know. I’d rather wait for the results of the human experiments, and then decide.

Epilogue

My estimate is that to carry out the required experiments in humans would cost about $10-20M. To develop and clinically test an NPY inhibitory drug could cost anywhere from $50-100M. Can the health care mavens quickly calculate what would be the ROI (return on investment) on this sum?

By Dov Michaeli MD, Ph.D

Who hasn’t complained about loss of memory? With increasing frequency, I forget where I left my glasses, what’s her name? Where did I meet him? And for the hundredth time, what’s the name of this bird?

No, it is not incipient Alzheimer’s. I still write blogs, although that’s no proof of a sound mind. I manage a large drug development project, read the newspapers daily and am up on the latest political twist. So what’s going on?

Beware received wisdom

When I went to medical school (UCSF) I was struck by a paper I read claiming that 50% of what we were taught would be either obsolete, or plain wrong, within 5 years; amazing, but true, and not very reassuring to both physician and patient. One of the things I was taught with great certitude was that with age we progressively lose neurons, which make up the gray matter in the brain. True enough even today. It was then a no brainer to conclude that this loss of neurons is responsible for the creeping loss of cognitive function in the elderly. This tidbit of “information” turns out to be part of the 50% that is obsolete, and maybe even wrong.

The nerve cell

A neuron, like any other cell, has a “body”, enclosed by a membrane. It contains a nucleus, where DNA resides, mitochondria, the power plants that provide energy for the functions a neuron performs, and cytoplasm, where proteins are shuttled about and enzymes perform what they are supposed to. But then there is something unique to neurons: they have long projections, some of them inches long (which is enormous in the context of microscopically small cells). These long projections, called axons, serve two purposes: they serve as conduits for a traffic of neurotransmitters and other substances on their way out of the neuron. And, through tiny projections coming off their surface, called dendrites (small branches, in Latin), they make contact with other neurons around them. This is how information, in the form of electrical impulses, is passed around the brain along precisely demarcated circuits and over very long distances. The neuronal cell bodies, where the nucleus and the DNA reside, are the “brain” of the cell; they have a gray hue under the microscope—hence “gray matter”. The axons, on the other hand, are considered conduits only, very much like water or sewer pipes—no “brain” at all. They have a white hue, and are called the “white matter”.

Organization of the brain

The human brain can be divided into major functional regions, each responsible for different kinds of “applications,” such as memory, sensory input and processing, executive function or even one's own internal musing. The functional regions of the brain are linked by a network of white matter conduits. These communication channels help the brain coordinate and share information from the brain's different regions. White matter is the tissue through which messages pass from different regions of the brain.

Scientists have known that white matter degrades with age, but they did not understand how that decline contributes to the degradation of the large-scale systems that govern cognition.

So what’s new?

New research, published December 6, 2007, in the journal Neuron, begins to reveal how simply growing old can affect the higher-level brain systems that govern cognition. The research was conducted by Randy buckner’s group at the Harvard Medical School and the Howard Hughes Medical Institute. As Jessica Andrews-Hanna, a graduate student in Buckner's lab and the lead author of the study stated:
“The crosstalk between the different parts of the brain is like a conference call; we were eavesdropping on this crosstalk and we looked at how activity in one region of the brain correlates with another.”
Buckner, Andrews-Hanna, and their colleagues looked at crosstalk in the brains of 93 people aged 18 to 93, divided roughly into a young adult group (18-34 years old) and an old adult group (60-93 years old). The older participants were given a battery of tests to measure their cognitive abilities—including memory, executive function and processing speed. Each person was studied using functional magnetic resonance imaging (fMRI) exams to measure activity in different parts of the brain. fMRI can precisely map enhanced blood flow in specific regions of the brain. Increased blood flow reflects greater activity in regions of the brain that are utilized during mental tasks.
For the task used in the Neuron study, subjects were presented words and were asked to decide whether each word represented a living (e.g., dog) or nonliving (e.g., house) object. Such a task requires the participants to meaningfully process the words.
Buckner's group explored whether aging in the older group caused a loss of correlation between the regions of the brain that — at least in young adults — engage in robust neural crosstalk.
They focused on the links within two critical networks, one responsible for processing information from the outside world and one, known as the default network, which is more internal and kicks in when we muse to ourselves. For example, the default network is presumed to depend on two regions of the brain linked by long-range white matter pathways. The new study revealed a dramatic difference in these regions between young and old subjects. “We found that in young adults, the front of the brain was pretty well in sync with the back of the brain,” said Andrews-Hanna. “In older adults this was not the case. The regions became out of sync and they were less correlated with each other.” Interestingly, the older adults with normal, high correlations performed better on cognitive tests.
According to the authors, it is inferred that in a young, healthy brain, signals are readily transmitted by white-matter conduits. As we age, those conduits are compromised. Depending on the networks at play, the result may be impaired memory, reasoning or other important cognitive functions. Buckner and Andrews-Hanna emphasized that other changes in the aging brain may contribute to cognitive decline. For example, cells' ability to express chemical neurotransmitters may also be compromised.

My take

1. Extremely important work. The dogma that “dropped neurons” is solely responsible for the cognitive deficits of normal aging simply did not make sense. First, the billions of neurons in the brain have plenty of capacity to make up for losses; we have a tremendous reserve. Second, the brain has the capacity to reroute specific information through alternative circuits if the original ones are compromised in any way. This is what underlies the phenomenon called “brain plasticity”, which is the basis for rehabilitation of stroke victims, or the educational strategies for dyslectic children.

2. This finding, like any in science, raises new questions. What is the nature of the disruption in the default network? Is it reduced number of axons due to neuronal death? Is it a functional defect in the conductive properties of the axons? Is the dysfunction generalized or restricted to specific pathways? What is the root cause of the changes? How can they be avoided?

What can we do about it now?

No doubt you have encountered claims of “brain rejuvenation”. Just work on your daily crossword puzzle, learn a new language, solve sudoku puzzles, stand on your head. The trouble with all these is that they work—but very specifically. If you do your daily crossword puzzles or sudoku you’d be good at them, but you will still forget names and misplace your car keys.

So far, the most convincing global change in the aging brain is reduced blood supply. Blood vessels either get occluded (atherosclerosis) or degenerate because of death of tissue they had supplied. Not surprisingly, the only strategy that proved effective in maintaining the overall integrity of cognitive function is, you guessed it, increase blood supply through aerobic exercise.

So throw away your sudoku puzzle or crossword puzzle and go out for a brisk walk or run. And don’t forget the keys to the house.

Dov Michaeli MD, Ph.D is in the biotech industry.

By Dov Michaeli MD, Ph.D

An article in the Sept. 17 2007 issue of Time magazine tweaked my interest. In it the author, John Cloud, argues that the recent crop of Republican homosexual legislators deserves our understanding of their weakness, rather the opprobrium of hypocrisy. To quote Cloud, he is offering “a moistly liberal request: Can we have a moment of pity for moralizers who fall?”

His argument runs as follows:

“Hypocrisy is among the most universal and well-studied of psychological phenomena, and the research suggests that Craig, Haggard and the others may be guilty not so much of moral hypocrisy as moral weakness. The distinction may sound trivial at first, but as a society, we tend to forgive the weak and shun the hypocritical.

Assume for a moment that Craig and Haggard actually believed what they said--that homosexuality is sin. They spent most of their lives fighting for the conservative cause. But in Craig's case, the Idaho Statesman has published allegations that there were at least three other slipups involving men, beginning in 1967. What if, like the radio host who gets fat but commits to losing weight, the moralizers were trying through their "pro-family" endeavors to expiate their lustful sins? You may think they are wrong about homosexuality (I do), but that doesn't make them hypocrites.”

With all due respect, this argument is not “moistily lliberal”, it is down right wrong on scientific and moral grounds.

What did  Larry (wide stance) Craig actually say? Here is one quote: “It is important for us to stand up now and protect traditional marriage, which is under attack by a few unelected judges and litigious activists”. Here is a man who married a woman and for decades fought against equality for gays.

So that we are not accused of picking on one unfortunate soul, remember Mark Foley?

Here is what he said: “For those pedophiles and predators across this country that have harmed or are considering harming a child, let me tell you that you are on notice… Your days in the shadows are over.” How prophetic, and how poetically just. This is the stuff Greek tragedies are made of.

Is it classical hubris, or is it hypocrisy?

The classical Greeks did not have Freud to kick around. They attributed human failings to hubris, a cardinal sin in the eyes of the Olympian gods. And the retribution that followed was swift and merciless. No moistily liberal excuses for them.

Two thousand years later, Shakespeare took a more nuanced approach to human failing. The hubris of the proud and vain King Lear had to be paid for, and dearly. But the process of suffering cleansed him of his hubris and opened his heart to love. His tragic death broke the hearts of millions.

Enter Freud, about 300 years later. His original psychoanalytic theories have been largely discredited, but the psychobabble residue they have left behind is still with us. Hence the “psychological” and moral sleight of hand a la Cloud: these people are not hypocritical at all, they are just weak.

Neurobiology refutes this argument

A recent review in Science (“Social Decision-Making: Insights from Game Theory and Neuroscience”) makes the point that social decision-making is controlled by a complex network of centers in the brain. The middle area of the prefrontal cortex (MPFC) and the area just below it (the orbitofrontal cortex, or OFC) constitute the “executive center”, making final judgments that balance inputs from the anterior and posterior cingulate cortex (ACC and PCC) which are the reward areas, and from the amygdala and the insula (AMY and INS), which process the more primitive urges, such as fright, aggression, hatred, rage, etc (Dr. Freud, is this the anatomical locus of your concept of the “subconscious”?).

What is important about this new research is showing the part of emotions in the overall mix of inputs into our decision-making. And this brings us to a potential explanation for what is called “cognitive dissonance”. What is meant by that is the nagging, and sometimes profound discomfort we feel when our behaviors don’t align with our beliefs. Our prefrontal cortex will keep nagging us, disturbing our peace of mind, interfere with our sleep, afflict us with unpleasant dreams—until we bring our behavior into alignment with our beliefs, which in reality are the products of the judgments made in the prefrontal cortex.

I accept that if you say one thing and then do another, the cognitive dissonance you will suffer is a result of your weakness. But when you do one thing and then say another—this is no weakness, this is willful hypocrisy. Larry Craig did not become a homosexual last month or last year. He was probably gay before he was a senator. Science tells us that he probably was born a homosexual. Mark Foley didn’t discover children when he first saw a congressional intern. They were most likely the objects of his desire decades ago.

Which leads me to the most “unmoistily liberal” conclusion: these people are hypocritical. The excuse of weakness or “the devil made me do it” doesn’t wash: Your prefrontal cortex warned you time and again that your behavior is reprehensible; you chose to ignore it. You did one thing and then chose to say or do something antithetical, in order to advance your political career. If the consequences began and ended with you alone—nobody cares. But your decision-making had social consequences. Your words, votes, actions— they inflicted grave harm on innocent people who have done you no wrong.

Dov Michaeli MD, Ph.D is in biotech and brooks no B.S.

By Dov Michaeli MD, Ph.D

No, I haven’t become a “new age”, “positive thinking”, “psychic energy” guy. I have seen a lot of willpower, grit and optimism overcome physical limitations—but that does not correct a physical limitation. Wouldn’t a way to change the brain’s perception of pain, or alter the brain’s pathways that determine an addictive behavior be a better solution than the panoply of drugs that we addle our brain with?

Technology to the rescue

One of the advantages of living in Northern California is being plugged in to the new and emergent technologies that are all around us. Superb universities that are incubators of revolutionary ideas, startup companies budding all over the place like mushrooms after the rain, many of them folding, other going on to do great and wonderful things (heard about the latest one? It has a funny name, something like Google)—what an exciting time and place to live in.

So it was really just a question of time before somebody took a stab at exploiting the brain’s plasticity (its adaptability or capacity to change) in order to deal with medical and psychiatric problems. Indeed, several startups are already hard at work doing just that.

How do they do it?

The technique of fMRI or functional MRI measures the blood flow in different regions of the brain, and displays it on a screen. This is how radiologists can determine areas in the brain that are metabolically hyperactive (pain perception, hunger, thinking) or hypoactive (stroke, some tumors). But now, a few companies are developing ‘real-time fMRI’, which means that you can view your own brain MRI in, well, real time. And that opens up some exciting possibilities.

Remember the old EEG (electroencephalogram) biofeedback technology? Subjects would be hooked up with electrodes which measure electrical feedback across the brain. They would then use a visual representation of the brain waves to control their blood pressure, for instance, using techniques of biofeedback such as meditation or visualization. The results were encouraging but were not translated to clinical use.

The new fMRI technique actually shows the subject which areas of the brain have increased blood flow if they suffer from chronic pain, for instance. The patient lies inside the scanner and watches a computer-generated flame projected on the screen of virtual-reality goggles; the flame’s intensity reflects the neural activity of regions of the brain involved in the perception of pain. Most people can control the flame’s intensity by concentrating and using visualization techniques. One could imagine bathing the neurally active region with a soothing drug, or dousing the area with a cold liquid, the flame would wane and patient would feel relief of the pain. Amazing but true.

This is actually an old concept. Paul Eckman, a professor of psychiatry at UCSF, wrote extensively about the mutual interaction between the body and the brain. We know, for instance, that a happy thought brings a smile to our face. But he showed that conversely, using the facial muscles involved in smiling activates the pleasure/reward centers in the brain. Result: you feel happy for no reason at all. Just try smiling every morning, or singing “Oh, what a beautiful morning” when you get out of bed, and you’d be amazed at the results. I read a few years ago about an Indian man who would go out to the park, and would laugh out loud without any reason. He claimed that it put him in a happy frame of mind for the rest of the day. Soon, other people joined him. They formed a laughing club, meeting daily in the park. This laughter became infectious, and thousands of people around the globe formed their own clubs. Sounds wacky, but it works, and it has a neurobiological basis. Try it!

The possibilities are mind boggling

What else can be controlled?

• I already mentioned the craving for drugs; addiction should be eminently amenable to this technique, since it is restricted to distinct brain regions.
• Hunger and feeding control.
• Psychiatric diseases such as depression.
• Behavioral disorders, such as uncontrolled anger, fear, phobias.
• How about stroke? Recent experiments have shown that by forcing stroke patients to use their paralyzed limb rather than the functional one, they begin to regain function. Underlying this “miracle” is the capacity of the brain to adapt and generate new pathways to serve the functions of the damaged ones. One problem with these experiments is that improvement is painfully slow and uneven. It is quite plausible the visualization of the new areas, which should have increased blood flow, could improve the outcome of these experiments.

I am sure that assorted libertarians and privacy watchdogs will warn about the sinister possibilities of this kind of brain control. Frankly my dear reader, I don’t…Just smile and be happy.

Dov Michaeli MD, Ph.D is in the biotech industry and is engaged in development of pain control medication.

We modern humans have a tough time curbing our appetite. The reason for that is that our primitive ancestors, leading a life of hunters/gatherers (or scavengers, as recent research suggests) did not have a steady, predictable supply of food. So our physiology has evolved to store calories when we could get them, in the form of fat. The need was to maximize conservation of energy (or calories), and an elaborate system has evolved in the gut and the brain to accomplish that.

This state of affairs served our species well until relatively recently. When the industrial revolution arrived about 200 years ago, farms became more efficient and produced more food, people became more affluent working in factories and offices, being able to afford the cornucopia of food and drink. At the same time work, and life in general, demanded less and less effort (or expenditure of calories).The consequences are evident today on every street of the industrial world. Unfortunately, our metabolism has not been able to adapt to this relatively recent change in lifestyle. Such things require an untold number of genetic mutations and take thousands of generations.

Is there nothing to be done about it?

The only way we can change our metabolism is through drugs. So far, all the heavily promoted and hyped diet pills, which are basically attempts to change our metabolism chemically, have been either very limited successes, or total failures. Fortunately, we are a species endowed with a high degree of awareness and the capacity to quickly adapt through changes in behavior. Remember Pavlov’s drooling dog? We are better. Being aware of what triggers our brain to send ‘hunger’ signals allows us to counteract them through behavioral strategies.

The biological clock

No, this is not really a ticking clock; but, biologically speaking, a lot more powerful. A clock is neutral, it just keeps time. There is no inherent functional meaning to 3AM or 3PM. It is us who invest it with the meaning of afternoon or early morning. The biological clock, on the other hand, doesn’t only tell time, it gives time a meaning. For instance, around 6 PM I get terribly hungry. Or around 6:30 AM I wake up regardless whether I got enough sleep or not. And when I travel across time zones, either to Europe or the Far East, my biological clock and my whole physiology still lives in California, and is totally screwed up.

We can see then, that this clock actually controls much of the brain function. One of these functions is the sensation of hunger. I am used to eating breakfast at a certain time of the day, and if I don’t get it I feel that something is missing, I am unhappy and miserable to be around, I can’t function at peak performance. If you think about it, the clock didn’t just control hunger, it controlled mood (great omelet--happy; it’s 11 AM and I haven’t had my breakfast yet--unhappy).

The nice thing about this all-powerful clock is that it can be trained to suit our whims. Try skipping lunch and the first few times will send you trawling for food the whole afternoon. But after a while, your need for lunch becomes less and less urgent until eventually you really don’t feel the need to eat in the middle of the day. But don’t carry it too far. I am reminded of one of my professors at UC Berkeley ( who will remain anonymous for obvious reasons), who studied the metabolic effects of calorie deprivation in the German cockroach (Blatella germanica; and I am not making this up). He slowly habituated the critters to a progressively lower calorie diet. One morning he came to the lab and was dumbfounded to find his meticulously habituated cockroach colony totally, irreversibly dead. Theories as to the causes ranged from the sublime to the ridiculous. To my simple-minded suggestion that they may have died of run-of-the-mill starvation, he responded plaintively,” but they have already got used to it…”.

Sight and smell

Why are the French such foodies? My theory de jour: it’s the presentation. When we walked in the market in Beijing and saw row after row of hanging Peking ducks at the butcher shops, I was mildly disinterested. But when they wheeled in the duck in a fancy restaurant the thing looked irresistably delicious and we devoured the whole thing. How do you think did Ray Croc make McDonald’s such a success? He stood outside a small hamburger diner and took in the smells. He immediately knew that he stumbled upon a winner, bought the restaurant and its formula for Freedom (aka French) fries and hamburger patties, and the rest is, as they say… fat kids with diabetes. Both the rhinencephalon (or the smell center) and the visual cortex communicate with the hypothalamus, the area in the brain that controls hunger, through extensive neural connections.

Don’t eat when you are cold

One of the important functions of our physiology is to maintain normal body temperature. For instance, the shivering response to cold is a way for the body to raise its temperature. Metabolism creates heat, and when we are cold the normal response is to eat more, and more frequently. That’s why we tend to eat more in the winter (and, alas, gain more weight) than in the summer. Can you imagine yourself being ravenous on a 100° day? All I can think of is crushed-ice margaritas.

What can we do?

The answer is: a lot. The biological clock and the relationship between smell, sight and hunger are all subject to habituation, or more plainly—to our will. This is literally the old 'mind over body', and all we need is the will and the persistence.

And yes, don’t forget to heat up the house before you sit down to dinner.

Dov Michaeli MD, Ph.D

A few weeks ago (May 9, 2007) we posted a comment on Gina Kolata’s article in the New York Times (May 8, 2007) The article basically laid the blame for the obesity epidemic afflicting us at our genes. Kolata reviewed work suggesting that genes are involved in obesity, with the implication that a fight to lose and maintain a lower weight is not only excruciating, it is practically futile.

That simply didn’t sound right. At least 10 genes have been discovered thus far that are involved in obesity and diabetes; more are bound to be discovered. We also know that the US population is fast approaching the 50% mark of overweight (BMI 25-29.99) or obese (BMI > 30). These genes presumably are not recent mutations. Why is it then, that only relatively recently did these genes express themselves to cause the outbreak of obesity? I think the answer is quite obvious: we have here a classic case of genetic/ environmental interaction. The genes have been there all along; they haven’t changed. The new elements that caused such a massive upward shift in BMI are the invention of the car, television, computers, all leading to a sedentary life style. Couple this with profound changes in our dietary and eating habits, resulting in a significant increase in caloric intake, and you’ve got an inescapable outcome: weight gain.

Don’t go shopping for food when you are hungry

I don’t know who first pronounced this maxim, but I am sure many of us rediscovered it many times, independently. What we actually discovered is that hunger is such a powerful physiological drive that no rational, moderating influence can keep it in check.

The hunger drive

Our gut reaction, so to speak, to hunger is primarily hormonal. Fat cells secrete a hormone, leptin (leptos means thin, in Greek), that travels to the brain, and signals a message of satiety; the more leptin, the less hunger. Another hormone, called ghrelin is secreted from the stomach when it is empty, and its signal to the brain is hunger; the more ghrelin, the more hunger. This description is obviously a vast oversimplification, but the basic mechanism is clear: our sense of hunger or satiety is a balance between hormones with opposing influences on the center in the brain that controls feeding. This area, called the hypothalamus has neuronal connections to two other important areas: the amygdala, and the nucleus accumbens. Activation of the amygdala, when the hypothalamus senses hunger, causes a sense of alarm, sometimes accompanied by aggressiveness, easy irritability and other hard-edged feelings. On the other hand, a sense of satiety and fullness activates the nucleus accumbens, which is the seat of all the warm and fuzzy feelings, like reward and pleasure. The neurotransmitter that mediates this sense of pleasure is dopamine.

The cocaine connection

It turns out that dopamine is also secreted in the nucleus accumbens in response to cocaine, amphetamines and other recreational drugs. In fact, the response of the cells that carry the dopamine receptors to the sudden rise in dopamine concentration is to reduce the number of receptors, so as to keep the stimulus within manageable bounds, so to speak. This phenomenon is called receptor downregulation. To keep the pleasurable sensation at its previous level one needs to take even more cocaine, which in turn causes even more downregulation. You can readily see the neurobiological downward spiral that we call addiction.

Lo and behold, the same pattern is seen in brain scans during binge eating: Surfeit of dopamine, activation of the nucleus accumbens, and downregulation of dopamine receptors.

The brain’s “adult supervision”

Of course, being civilized creatures we could not let ourselves be governed by such “primitive” drives as pleasure and reward on the one hand, or anxiety, aggression and rage on the other. Indeed, evolution endowed us with a highly developed area in the brain called the prefrontal cortex. This is the seat of judgment and rational decision-making. It weighs the messages arriving from the reward and anxiety centers and renders judgments that find their expression in what we call behavior.

However, this Solomonic wisdom does not always prevail. When exceptionally strong messages arrive from one center, they overwhelm the messages from the other, and the judgment of the prefrontal cortex becomes skewed, or completely overwhelmed by the flood of the incoming powerful signals. Each one of us, after along period of fasting, must have felt an overwhelming desire to binge-eat. Only when we are finally disgustingly stuffed, do we ask ourselves: what am I doing? In neurobiological terms, the storm of signals from the amygdala (hunger to the point of anxiety) and the nucleus accumbens (“how sweet it is”, and the hell with the diet!) subsided, and the ever stern, judgmental prefrontal cortex reasserts itself (“have you no shame?”).

So, is it genes or addiction?

I believe that the addiction model is a more plausible explanation of the overeating epidemic that is afflicting us now. It also explains the extreme difficulty in “kicking the habit”, losing weight and maintaining it over a long period of time. As any recovered drug addict will tell you: one never really kicks the habit; it is a constant battle, and one is always on the brink.

The encouraging aspect of this grim picture is that addiction is susceptible to therapeutic intervention. There are drugs that can blunt the addictive urge. For instance, the drug naloxone reverses the effects of morphine. Interestingly, naloxone also blunts the hunger drive and reverses binge-eating.

Dov Michaeli, MD, Ph.D

If you enjoyed reading this, you may also want to read:

• Obesity:  The devil made me do it
• Genes and food -- good and genes

Last week we looked at the complex interactions of genes, brain circuits, hormones, psychology and culture in forming the mass killer’s persona. But keep in mind, most killers don’t have genetic or anatomical defects that we know about, although some new ones may be discovered in the future.

Obviously then, psychology and culture must be playing a major role in the seemingly unprecedented wave of violence we are experiencing.  Unprecedented? Not quite.

Scriptural violence

Here are a few choice nuggets from the Bible:

• Lot , a pious man living in Sodom, took into his home some traveling strangers who stopped for the night. No sooner than did the men retire for the night, a rumor spread around town that the men were homosexual.
  The destruction of Sodom and Gomorrah by John MartinThe enraged Sodomites assembled in front of Lot ’s house and demanded that he surrender his guests. When he refused, they forced their way in and, well, sodomized them. The first recorded anti-gay crime. But unlike today, the punishment was swift and terrible: God rained fire and brimstone on the town and obliterated it off the face of the earth. Don’t worry about Lot , God warned him to leave immediately.

• Moses, who spoke to God himself, transmitted His injunction to “wipe the Amalekites off the face of the earth”. Who are those terrible Amalekites that deserved what we call today ‘genocide’? They apparently were a nomad tribe in the desert who raided the Israelites as they made their way to the Promised Land. In fact, Moses was denied entry to Canaan, according to a later biblical exegesis, after leading his people in the desert for forty years, because he failed to completely annihilate them.

The story of the concubine in Gibeah: an academic study.

The Concubine of Gibeah 3 by Janet ShafnerThere once was a man and his concubine from the tribe of Ephraim who were traveling in the land Benjamin, another Israelite tribe. As the couple dined in the city of Gibeah , a mob assembled outside and pounded on the door. The mob captured the concubine, then raped and beat her to death. The man collected her corpse the next day and traveled home. The other tribes of Israel were outraged at the crime, assembled an army and razed several Benjaminite cities, killing every man, woman, child and animal they could.

Brad Bushman, a social psychologist at the University of Michigan in Ann Arbor, is the lead author of a study, "When god sanctions killing: effect of scriptural violence on aggression," published in the March issue of Psychological Science (vol. 18, pp. 204-207; 2007).  He had about 500 students read the tale about the tribe of Ephraim in order to study the role of “higher authority” in the propagation of religious violence. For half the students he added another passage:

When the man returned home, his tribe prayed to God and asked what they should do. God commanded the tribe to “take arms against their brothers and chasten them before the Lord”.

The students then took part in an exercise designed to measure aggression. About half of the study participants were from Brigham Young University , and almost all of them were religious Mormons. The other half were from the Free University in Amsterdam . Of the Dutch group, only 50% believed in God, and 27% in the Bible (astonishingly high percentages, for Europeans).

But for both groups, regardless whether they lived in the U.S. or the Netherlands , or whether they believed in God or not, the trends were the same:

Those who were told that God had sanctioned the violence against the Israelites were more likely to act aggressively in the subsequent exercise.

What does the study mean?

First, what it doesn’t mean: one cannot conclude that religious people are more aggressive than non-religious people. But it does suggest that people are more prone to aggression when they feel that it is sanctioned by some higher authority, be it God, or his clergy.

Jihadist terrorism and the silence of religious authorities.

One could quote passages from the Bible and the Koran that would make it sound like these were manifestos of some violent cults. In fact, modern religion tries to de-emphasize the violent aspects of the scriptures. The story of the Amalekites was edited out of many versions of modern Hagaddahs, and in others its violent message is softened with an injunction to be charitable to the stranger among us. But with the notable exception of a few courageous Moslem women, there is a deafening silence coming out of the religious community. The feeble voice of moderate Moslem clergy and intellectuals is almost invariably accompanied by their loud protestations of American aggression or Western social permissiveness. Western clergy and intellectuals, being "sensitive" and "politically correct", are not much better—they are experts at diffusing the responsibility: it is not the religion and its leaders that are at fault; it is the “root causes” whatever they are, it is poverty, or Western cultural imperialism, or insensitivity and intolerance toward other cultures. It fell to a Saudi security official to state, after reporting the foiling of a vast Al Qaida plot and the arrest of 172 young jihadists, to add: "unless we change the ideology (of religious extremism), more young people will fall pray to terrorism".

If we ever needed rigorous academic proof that religious authorities can, and sometimes do, propagate aggressive and violent behavior—now we have it in the study by Bushman and his coworkers.

It is time to speak up and tell the unvarnished truth—a culture that justifies violence in the guise of religion is intolerable in the 21^st century. Religious leaders need to raise their voices against this perversity.

Genes

In 1993 scientists reported on a Dutch family, 14 members of whom were sociopaths, involved in aggressive crimes such as bullying, physical violence, rape, and arson. They all had in common a mutation in a gene that makes an enzyme called MAOA. The function of this enzyme is break down neurotransmitters such as serotonin and noradrenaline (or norepinephrine, a chemical first cousin of adrenaline). The ready conclusion was: defective enzyme caused elevated level of serotonin and noradrenaline, resulting in overactive brain circuits that serve aggressive behavior.

Case closed? Not so fast…

In a wonderful summary of the topic in Newsweek magazine ( April 30, 2007 ) one of my favorite writers on the subject, Sharon Begley) describes a 2002 study in New Zealand of 442 men who were followed since their birth. Indeed, men with low MAOA were more likely to engage in persistent fighting, bullying, cruelty and violent crime. But not all of them; only men who had been neglected or abused as children fit the bill. Men who grew up in a normal environment exhibited none of the violent traits.

Neuroanatomy

In previous postings we waxed scientific about the amygdala, two almond-shaped structures deep inside the brain, that are the seat of primitive emotions such as rage and fear; these constitute the emotional basis of the fight or flight reaction, which is mediated by noradrenaline. These waves of seemingly overwhelming emotions are checked and inhibited by another, more modern structure in the brain: the prefrontal cortex. This structure is the seat of judgment, planning, abstract thinking. It inhibits inappropriate or impulsive behavior, and is engaged in constant self-monitoring (could it be the anatomical seat of the Freudian super ego?). So in typical Ying/Yang fashion, the outcome of our behavior must then be the product of the amygdala and prefrontal interaction. Remember the then famous case of Kip Kinkel, a 15 year old who in 1998 killed his parents and two dozen schoolmates in Springfield , Oregon ? His brain scan showed a completely silent prefrontal lobe; he had nothing to check and balance his raging anger emanating from his amygdala.

Is this it? Not quite…

Hormones

Women love to point out, without much evidence I might add, that men’s aggressive behavior can be traced to their testosterone-addled brain. Only partly true. The level of testosterone is within normal limits between 20% and 200% of the mean; that’s a huge range of normal. However, if the level of testosterone exceeds 400% of the mean, then indeed women are right—men with these levels are more prone to violence. In fact, testosterone is an equal opportunity hormone; in a species of hyenas (I forget which) the first newborn in a litter, be it male or female, will eat the rest of the brood within days of birth. It turns out that this vicious sibling has inordinately high levels of testosterone in its brain, much higher then the other hapless siblings.

But to assume that we are simple automatons, following helplessly the script written by our genes, brain circuits and hormones, would deny a self evident fact—we don’t behave automatically, we do have a certain degree of free will.

Psychology

The interaction of biology and the life one leads turns out to be of paramount importance in shaping the criminal mind. The most important characteristic of the behavior of mass killers is paranoia. They have the sense that the whole world is against them, that everybody but themselves is responsible for their troubles, that the world is unfair. They are usually depressed and socially isolated.

This kind of personality, you might say, could be the product of brain circuitry gone awry. But here is a fascinating finding from animal and human studies: behavior can change brain circuitry and function-- an outstanding example of nature/nurture interaction. So what are the non-biological roots of violent behavior? We finally arrive at the inevitable:

Society and culture

It is the social environment that allows, indeed encourages, psychopathic criminal behavior. Many societies have members with genes gone awry, with malfunctioning brain circuits, with males suffering from raging hormones, with children raised in violent homes. But, sad to say, we have the dubious distinction of being the champions of gun violence in the civilized world. In 2004 there were 29,645 deaths due to gun violence in the US , or 10.08 per 100,000. For comparison, France had 4.93, Belgium 3.67,and Spain 0.75 per 100,000.

In 5 years of war in Iraq about 3200 of our soldiers got killed. Yet, we tend to see the situation in Iraq as intolerable but we dismiss  the carnage in our own streets with a helpless shrug: "It’s the culture… "

We mentioned the case of Kip Kinkel. Yes, his prefrontal lobe did not do its job. But here is rest of the story: a psychotherapist actually suggested that his dad buy him a gun so they could have something to do together.

As Pogo said: we have met the enemy, and it is us.

Dov Michaeli MD, Ph.D

A recent paper in the Journal Nature, Damage to the Prefrontal Cortex Increases Utilitarian Moral Judgments  (Nature, advance online publication 21 March 2007),  has provided strong evidence that we are indeed moral animals, and that certain aspects of our moral behavior are hardwired in our brain. The institutions involved in this research (U. Iowa Dept. of Neurology, Harvard U. Dept. of Psychology, and the Brain and Creativity Institute at the U. Southern California) reflect the multi-disciplinary approach required for such a study.

Where in the brain is Morality?

Our brain is organized in layers, somewhat like an onion. The deepest layer, like the brain stem and the structures around it, is the most ancient, or primitive, from an evolutionary point of view. These structures control vegetative functions, like heart rate, breathing, gastrointestinal motility, etc. These functions are essential for life, and are shared by organisms from the most primitive to the most complex.

Next in evolution came another layer of behavioral complexity: diverse functions such as thirst, hunger, sexual attraction, fight-or-flight responses to danger, responses to day-light cycles, short and long term memories. These functions are mediated by structures deep inside the brain called the midbrain.  The midbrain contains structures, such as the amygdala (fight of flight, rage, aggression), the hypothalamus (hunger), the nucleus accumbens (reward, pleasure) and the hippocampus (memory). These functions are not voluntary; they are found in mice and humans alike.

A more recent layer of the brain tissue, called prefrontal cortex, was added when monkeys started to evolve. In this layer resides the ability to function as a social animal, for instance traits like empathy and moral judgment. The last and outermost layer, added relatively recently, is called the frontal cortex.  It is most developed in humans. Messages from the brainstem, midbrain and prefrontal cortex feed into this area (situated right behind the eyes), where they are all integrated, weighed, judged, contemplated—and then translated into action.

What did the Nature paper find?

It has been suspected for about 10 years that an area within the prefrontal cortex, called the ventromedial prefrontal cortex or VMFC, is required for emotions and moral judgments. When subjects in a brain imaging study were presented with a scenario requiring moral judgments, the area that lit up was the VMFC. What kind of situations were they? Highly aversive ones; for instance, sacrificing one person in order to save several other. The anguish of such decisions is captured in Sophie’s Choice, or in King Solomon’s famous trial of the two women.

The vast majority of people will recoil from making a “utilitarian” calculation of killing one person so as to save others. Indeed, in this experiment over 80% refused this option. But in a group of 6 patients who had some kind of pathology in their VMFC, such as an aneurysm or a tumor, the judgment was completely utilitarian—kill the few to save the many. No hesitation, no compunction. In fact, Antonio Damasio, one of the authors of present study, published a study in 1999 of two patients who have had a defect in their VMFC since infancy ( Nature Neuroscience vol. 2, pp. 1032 - 1037 (1999). As adults, the two early-onset patients had severely impaired social behavior despite normal basic cognitive abilities.  They showed insensitivity to future consequences of decisions, defective autonomic responses to punishment contingencies and failure to respond to behavioral interventions. The authors concluded: “Thus early-onset prefrontal damage resulted in a syndrome resembling psychopathy.”

What does it all mean?

The implications of these studies are enormous. For instance:

• We may finally get a handle on extreme psychopathic behavior, such as serial killing, serial raping, extreme levels of domestic violence.
• Our legal system will have to, sooner or later, come to grips with criminal behavior engendered by structural defects in the brain. Evidence of brain imaging (fMRI), is already being introduced in court, and juries are becoming receptive to the evidence.
• On a more hopeful note, but probably less imminent, we may learn one day how to intervene and enhance individuals' moral judgments. Wouldn’t that be a welcome development of this "1984 science?"

 Moral philosophers have dismissed evolutionary biologists and neuroscientists forays into the realm of ethical and moral judgment. They are now having second thoughts, and the more intellectually open and curious among them (a more developed frontal cortex?) are listening attentively. Can the days when vexing issues such as religion and faith in a higher being find a biological explanation be far off? Is conflict resolution between individuals and nations amenable to biological treatment? Science is what we make it to be. If we put it to good use it can promise humanity.

Dov Michaeli MD, Ph.D

A research group working at the National Institute of Mental Health has published a paper (February 8, 2007 issue of the “Journal of Clinical Investigations (JCI)”) that contributes important genetic information about the normal functioning of our brains, and also raises interesting possibilities regarding the malfunction that results in schizophrenia.

How do we exercise judgment?

One of the hallmarks of being human is the capacity to exercise judgment. Like all animals, we are given to ‘primitive’ feelings of fear, rage, anger, and also pleasure and reward. The negative feelings arise from the amygdala. These are small groups of nerves, or nuclei, deep inside the brain, located beneath the cortex (the outer layer of the brain) and above the brainstem. The positive feelings of pleasure and reward originate from an adjacent nucleus, the nucleus accumbens,  one of the basal ganglia (which also plays a major role in addiction).

The behavior of lower animals is governed by these nuclei. For instance, the “fight or flight reaction” that occurs when animals are confronted with a dangerous situation originates in the amygdala. It is automatic—and this is important as there usually is not enough the time to filter information and make a rational judgment in an emergent situation.

Thankfully, we “higher beings” have the capacity to exercise some judgment. Next to the amygdala and the nucleus accumbens is another group of neurons called the striatum. This part of the brain gets its name because it has the appearance of layered bands of gray matter. The striatum has projections to the basal ganglia and to the prefrontal cortex.

Now, things are really getting interesting. The prefrontal cortex is the site where all those ‘primitive’ stimuli are being vetted, controlled and modulated, in other words—judgments are made. This prefrontal cortex (also called prefrontal lobe) is located in front of our brain, right behind the forehead. This is a relatively ‘modern’ addition to the brain, and humans have the most generous sized prefrontal cortex of all animals.

What the NIMH scientists have found is that a certain variant of a gene called DARPP -32 optimizes the functioning of the connection between the striatum and the prefrontal cortex. It is found in 75% of people. This is a major finding, because it gives us the genetic basis for exercising judgment. Furthurmore, the fact that such a large majority of people possess this variant means that it is probably the most effective variant of DARPP, which is why it was selected for by the evolutionary process of natural selection.

What does all this have to do schizophrenia?

It turns out that exactly the same DARPP-32 variant that occurs in most normally functioning brains has been found to be also common in people with schizophrenia. The evolutionary implication of this fact is that by selecting the most advantageous DARPP variant to optimize the connection between the striatum and the prefrontal cortex , natural selection also selected for schizophrenia. Nothing is perfect in life.

But there is another, more clinical, implication. It suggests that the striatum itself is not the seat of the schizophrenia abnormality, since schizophrenics possess DARPP-32, the gene that optimizes its function.

The authors of the JCI article speculate that the schizophrenia defect then must lie in the prefrontal cortex, the area that filters and controls all those stimuli coming from the striatum. It is possible that everyone could have an underlying propensity to have hallucinations, but normally functioning prefrontal lobes suppress them. (Indeed, in sleep, when the prefrontal lobe is 'asleep' as well, we may have dreams that sometimes have an hallucinatory character). Not so for people with schizophrenia--there is no 'censor' there to check those 'unnatural voices', as the bard would say, rising from the depths of their brain to haunt them.

 Is this speculation rational? Absolutely. Is it right? Hard to say. Biology has a way of confounding us every time we think we have found “the answer.” Only time will tell.

Dov Michaeli, MD, PhD

Your weight is ultimately in your head by Dov Michaeli, MD, PhD After spending twenty years in the rarified atmosphere of academic research and teaching medical school, followed by a long stint in the biotechnology industry, I decided to revisit a subject I used to teach: energy metabolism. Wow! This was a culture “shock and awe”. Twenty years ago we used to teach our budding doctors the simple fact that if there are more calories in the diet than are burned by physical activity, the excess energy is stored as fat. We understood in great detail, the metabolic pathways by which food is used to provide energy and the excess converted to fat. When it came to overeating, the message we gave our students, and they in turn gave to their patients, was the equivalent of “just say no”.

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